hero-first-trimester

The ASPRE Trial

1ST TRIMESTER

A new era in pre-eclampsia management

ASPRE brought conclusive evidence about the efficacy of aspirin in prevention of preterm pre-eclampsia in women at high risk of the disease. PerkinElmer’s PlGF 1-2-3™ assay was used as part of the combined screening approach to identify those women at risk.

Overview
INITIAL RESULTS

Low dose aspirin for preventive care.

Results showed a 62% reduction in the incidence of preterm pre-eclampsia (before 37 weeks) and an 82% reduction in the incidence of early onset pre-eclampsia (before 34 weeks) in women who took 150 mg of aspirin each night from 11-13 weeks’ gestation until 36 weeks.

COMPLIANCE

Ensuring the best outcome

Secondary analysis of the ASPRE data further showed that the beneficial effect of aspirin depended on compliance. For women conscientiously taking more than 90% of the daily tablets, the reduction in the incidence of preterm preeclampsia (before 37 weeks) was as high as 75%, compared to 62% when any level of compliance was considered.

FURTHER ANALISYS

Better outcomes & reduced health care costs

Recent analysis of the ASPRE data also revealed that administration of 150mg aspirin at bedtime starting from 12 weeks reduced the length of stay in the neonatal intensive care unit by 68%, which was highly significant. This could be mainly attributed to a decrease of births at less than 32 weeks’ gestation.

ASPRE Questions & Answers

Aspirin related questions

Content edited and reviewed by

Dr. Liona Poon
Chinese University of Hong-Kong
The Fetal Medicine Foundation
Liona Poon contributed to a pan-European multicentre randomised controlled trial of aspirin vs. placebo in the prevention of pre-term pre-eclampsia (ASPRE), which was funded by the EC FP7 scheme. In the past 10 years she has focused her research on establishing a programme for effective early prediction and prevention of pre-eclampsia, which is a major cause of maternal and perinatal morbidity and mortality.

If a woman is already on aspirin at 12 weeks, we should still screen as we aim to provide individualised risk for each pregnant woman. One of the most likely reasons for why someone would be on aspirin before 12 weeks is conception by in vitro fertilisation and there is a possibility that the woman is on 75 mg aspirin, which is a suboptimal dosage and it might not be continued till 36 weeks.

As there is no other proven intervention, then expectant management would be appropriate. This would include frequent BP measurements to ensure early diagnosis of preeclampsia.

Other potential prophylaxes, such as Heparin and Metformin, could be considered, depending on why she is categorised as high-risk.

No overall increase of vaginal spotting was observed in the ASPRE trial. There was no significant difference in the rate of vaginal bleeding between Placebo and aspirin groups. During the trial, we did not advise women to stop the trial drug based on vaginal spotting.[1]

The rates of side effects, in particular upper gastrointestinal symptoms and bleeding, were not significantly different in women with BMI ≤25 kg/m2 and those with BMI >25 kg/m2. We therefore do not have data to support the recommendation for a lower dosage of aspirin in smaller women. A study by Masotti et al (1979) demonstrated that doses of 3.5 mg/kg of aspirin seemed to be able to induce maximum inhibition of platelet aggregation without significantly affecting prostacyclin production.[2] Suggested aspirin dosages based on maternal weight are provided in Table 1.

If aspirin is effective and ‘safe’ it should be given to those that would benefit from it the most. As Prof. Zarco Alfirevic commented on the NEJM website “a word of caution to all enthusiasts out there who will now start to advocate (near) universal prescribing of low dose aspirin in pregnancy. The FMF algorithm has identified an interesting phenotype which appears to respond to aspirin very well. We cannot and should not assume that all screen negative women will respond equally well to aspirin. Furthermore, current safety data are reassuring but still limited.“

The ASPRE screening algorithm, for the same screen positive rate as per NICE (The National Institute for Health and Care Excellence), identifies 75% of cases of pre-term pre-eclampsia.

It identifies a group of at risk women that responds to aspirin in the prevention of pre-term pre-eclampsia.

In addition, we should consider the issue of compliance. A study (McNulty et al, 2011) found that compliance with Folic acid supplementation was only 19% and led to the recommendation of fortification of food in many countries.[3]

Though aspirin is considered safe in drug trials, nonetheless, it is a drug with known side effects, and therefore high risk women for pre-term pre-eclampsia should be identified and compliance with aspirin prophylaxis should be ensured throughout pregnancy.

This is an indication of the level of compliance that can be expected in a motivated high-risk group of women, who are being actively managed by their physicians. Adherence according to trial group is presented in Table 2.

A new meta-analysis (Roberge et al, 2017) including the results of ASPRE, has confirmed that aspirin <100 mg/ day starting at any gestation, has no benefit. Aspirin ≥100 mg/day, started after 16 weeks has no benefit; whilst aspirin ≥100 mg/day, started before 16 weeks, has a major benefit.[4]

Clinical implementation questions

In essence the question is, what happens if the woman is screened positive by NICE guidelines, but screened negative by the FMF algorithm. We would manage her as a low risk case as a detail review of her biomarkers would indicate that they are normal. However, if the clinician feels strongly for aspirin prophylaxis, there is no harm in treating this woman with aspirin.

To achieve the best prediction and prevention of pre-term pre-eclampsia (<37wks), ideally screening should be done with evaluation of maternal history, measurement of uterine artery Doppler, mean arterial pressure and placental growth factor. In the absence of one or two of the biomarker(s), risk calculation can still be done but the detection rate for pre-term preeclampsia will be reduced, in turn leading to a reduction in the treatment effect size by the aspirin prophylaxis.

The algorithm has been validated for the 11–13+6 weeks gestation.

As a minimum a clinician could still use the NICE recommendation: if a woman is at high risk, she should be started on aspirin 150 mg/day.

This is a hypothetical situation. In ASPRE trial, we did not observe normalisation of the biomarkers with the use of aspirin. Aspirin should be taken from 11–13+6 weeks till 36 weeks.


Chronic hypertension is a major risk factor for pre-term pre-eclampsia. The risk is increased by a factor of 15.

Number of cases with chronic hypertension was small in the ASPRE study, therefore, it is too soon to draw a conclusion.

If the clinician feels strongly for aspirin prophylaxis, there is no harm in treating with aspirin. Appropriate management of blood pressure is also recommended.

The study was not powered for secondary outcomes.

To account for comparisons for multiple outcomes, 99% confidence interval was reported, instead of 95% confidence interval. Interestingly, we have observed strong trends in the direction of benefit with the use of aspirin, which are consistent with earlier publications.

adverse outcomes

If you screen 10,000 women, we anticipate 70 cases of pre-term pre-eclampsia (<37wks). 53 of the 70 cases will be detected by the ASPRE screening algorithm and 33 cases of pre-term pre-eclampsia will be prevented by aspirin prophylaxis. Therefore, the number needed to screen to prevent one case of pre-term pre-eclampsia is 303.

Given pre-eclampsia is a heterogeneous syndrome, it is unrealistic to expect a single screening test and treatment, to identify and prevent all cases of pre-eclampsia. It is clear that the ASPRE screening test identifies a specific phenotype of pre-eclampsia, which is linked to placental insufficiency. Though it focuses on a small proportion of preeclamptic cases, they are those that are associated with higher rates of maternal and perinatal morbidity and mortality.

In addition, these cases of Pre-eclampsia, constitute a significant cost burden to healthcare systems. This is illustrated by the analysis of Stevens et al, AJOG 2017 who reviewed the impact on the US Healthcare system[5] in Table 3.

estimated unit costs

Having now validated a screening test and confirmed a prophylactic option for women at risk of pre-term preeclampsia, future research will focus on identifying appropriate screening tests for term pre-eclampsia.

To achieve the best prediction and prevention of preterm pre-eclampsia, ideally screening should be done with evaluation of maternal history, measurement of uterine artery Doppler, mean arterial pressure and placental growth factor. In the absence of one or two of the biomarker(s), risk calculation can still be done but the detection rates for pre-term preeclampsia will be reduced, in turn leading to a reduction in the treatment effect size by aspirin prophylaxis.

The screen positive rate using the NICE guideline is the same as with combined screening in the ASPRE trial, 10%.

This means that the number of women at potential risk of anxiety is equal with both approaches. The major difference is that the ASPRE algorithm will identify about 75% of women who will develop pre-term pre-eclampsia versus 39% only, with the NICE guideline.

A training course is available on the FMF website (fetalmedicine.org). This is a 1 hour course, which provides all of the information necessary to be able to implement this screening. Different options are described, which allow for local challenges in implementation, with minimal impact on performance. It is not necessary to start with the full protocol, if there are local challenges to be addressed. It is however important to start offering the new model of screening, since regardless of which option is adopted, it is clearly offering women a better clinical service than current guidelines.

Twin pregnancy is considered as a moderate risk factor, according to the NICE recommendation. The risk of preterm pre-eclampsia is significantly higher in twin pregnancy, approximately 15%. The new FMF algorithm does include twin pregnancy as a risk factor. However, there is no data on the evidence of efficacy of aspirin in twin pregnancy.

If the clinician feels strongly for aspirin prophylaxis, there is no harm in treating these women with aspirin.

The percentage of patients agreeing to participate was unexpectedly high and in some respects, it was not surprising, that 10% reconsidered their decision and decided not to participate in the trial.

This outcome was not included in our Statistical Analysis Plan. However, the data is as followed:

  • In the aspirin group: 5 (0,6%) abruption, 1 with preeclampsia (not pre-term pre-eclampsia)
  • In the Placebo group: 10 (1,2%) abruption, 4 with preeclampsia (all pre-term).

Risk Assessment Questions

No, it is not correct.

In our prospective validation study including a study population of 25,797 pregnancies, with 180 (0.7%) cases of pre-term pre-eclampsia, 450 (1.7%) of term pre-eclampsia and 25,167 (97.6%) without pre-eclampsia. With a risk cut-off of 1 in 100, combined first-trimester screening for pre-term pre-eclampsia detected 76.7% (138/180) of pre-term preeclampsia and 43.1% (194/450) of term pre-eclampsia, at screen positive rate of 10.5% (2,707/25,797) and false positive rate of 9.2% (2,375/25,797). More detailed information is shown in the diagram below.

study_design

References

  1. Rolnik et al, NEJM 2017 Supplementary data
  2. Masotti et al Differential inhibition of prostacyclin production and platelet aggregation by Aspirin. Lancet. 1979 Dec 8;2(8154):1213-7.
  3. Mc Nulty et al (2011) Women’s compliance with current folic acid recommendations and achievement of optimal vitamin status for preventing neural tube defects. Human Reproduction. Vol. 26 (June 2011) 6, 1530 -1536.
  4. Roberge et al (2017) Aspirin for the prevention of preterm and term preeclampsia: systematic review and metaanalysis. Am J Obstet Gynecol. 2017 Nov 11.
  5. Stevens et. al. Short-term costs of preeclampsia to the United States health care system AJOG 2017
  6. Rolnik DL (2017) ASPRE trial: Performance of screening for pre-term pre-eclampsia. Ultrasound Obstet Gynecol. 2017 Jul 25. doi: 10.1002/uog.18816.
  7. Rolnik et al (2017) Aspirin versus Placebo in Pregnancies at High Risk for pre-term Pre-eclampsia, The New England Journal of Medicine. Vol. 377, 7.

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